Terms of Reference of the Working Group; Invitation to Submit:
 

Submission and Recommendations to the Working Group by Prof. J. D. Pettigrew FRS

Preamble and Apologium:

It is a passionate article of faith for most neuroscientists that their labours may ultimately be of relevance to human concerns, such as mental health. My own translational research certainly reflects that passion, as it involves daily interactions with the brains of both human sufferers and animal models. In addition, my own manic-depression provides added insights, particularly when one considers the extreme sensitivity to small nuances that characterises the bipolar brain (see my concluding remarks about Virginia Woolf below). I  therefore believe that I should be on strong ground in claiming a special interest and expertize in the neuroscience/mental health nexus.

Given those facts about myself, I ask the reader to try to put themselves in my position when reading my submission. It cannot be doubted that I want to see neuroscience receive the support that it deserves. Yet I am under tremendous pressure that I might be accused of causing dissension in the ranks of neuroscientists as I point out the potential flaws in the process so far. Should I sit mutely by, upping my medication, if I feel that that the present (?only) opportunity could be missed because most Australian neuroscientists will take exception to the unrepresentative way in which the Working Group appears to have been constituted? What of the possible odium that might be attached to the golden neuroscience/mental health nexus if there is a general perception that the best and brightest minds had been passed over in favour of lobbyists ?

Public Perception of the Opinions Represented by the Working Group:

I am afraid that theWorking Group will not be seen to have been constituted in a way that properly reflects its own goals.  I provide some reasons for this below, along with recommendations.

1. Breadth and Bias:
 The constituency is narrow, with an over-representation of the NSV Ltd (Neuroscience Victoria). This company has used strong Victorian State backing recently to try to establish hegemony in neuroscience, in a way that is disturbing to many Australian neuroscientists who pride themselves on their eclecticism and diversity and who view with concern the claim (see NSA Ltd website) that they represent Australian neuroscientists, a misperception of which the Chief Scientist, Robin Batterham seems to be unaware.
 Even if one swallows all of the Wills Report logic about the need for Australia to consolidate its research efforts, (which I do not, citing the obvious success of our larrikin kind of creativity in the past), there remains the question of how one makes the decision about where to concentrate. That decision is looking a bit self-serving in the Victorian case.
 The excuse that the schmooging element that is apparent in the composition of the Working Party was a product of time pressures is not compelling. Even when one takes into account the special circumstances of these Prime Ministerial initiatives, the general public is not going to buy such an explanation for the bias, given our shrinking planet of enormously improved communications.  A preliminary analysis suggests that emails were sent out first to close associates of the Working Party and only much later to the most distinguished neuroscientists working in the mental health area, if they were contacted at all.

Recommendation 1:
In view of this evident bias, the Working Group should not be able to make any specific proposals about organization (item 4 on the terms of reference), particularly  along state or national lines, unless it has been reconstituted to reflect a more eclectic balance of national interests.

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2. Fundamental Research Needed:
In the context of choosing where to place resources in mental health, Prof. Harvey Whiteford has drawn attention to the need for fundamental advances, which I suspect will not be produced, perhaps not even foreseen, by the footsloggers of which there seems to be a preponderance on the Working Group. This can be illustrated with an example from a biomedical field that has enormously changed our lives:- The whole field of molecular biology was begun in the US by a German foreign national, who had been trained by Schrodinger in quantum physics, and whose accent and strange habits in exploring sewers (where he discovered the T4 bacteriophage) were certainly not conducive to any ready acceptance by his peers, let alone funding. In its alacrity to choose its own buddies, the Working Party does not give us much confidence that it would be able to lift its horizons enough to recognize a 21st century Max Dellbruck of Mental Health in its midst.

Recommendation 2:
That whatever specific proposals are put forward to the Prime Minister, the Working Group emphasise the vital importance of basic research in all its forms for the future mental health of the nation. Action on this would have to include a reversal of the entrenched, debilitating,  (bipartisan) government policy of under-resourcing  Australian universities and a recognition that a strong separation of research and academic streams failed in the UK and has likewise not been the most successful model in the US .
 

3. Cooperation:

 Since bright young minds in the relevant neuroscience disciplines could appear and be nurtured anywhere in Australia, neuroscience should be encouraged in those places where quality research is being produced, not just those places which have established a historical lead or a size advantage. A wiser strategy than the current divisive attempts to achieve hegemony in neuroscience by political means would be the cooperative strategy used by the flora of SW Australia, as set down by Tim Flannery in The Future Eaters. By carefully coordinating their interlocking efforts, the flowering plants of this ecosystem succeed against the odds imposed by the scarce SWA resources to achieve unparalleled diversity and a high level of continuous output that would be impossible if each species acted in isolation. A similar cooperative strategy would be highly productive if it incorporated the diversity of Australian neuroscientists as they acknowledged and built upon their complementary strengths. One would also reap the potential benefits of applying the detailed knowledge of neuroscientists about complex neuronal interactions and neural networks to arrive at an optimally-cooperative and productive structure.

 Recommendations  3a,b,c,d:
a. That neuroscience be recognized as an Australian strength;
b. That neuroscience be established as a national priority, for the pursuit of the fundamental new information required for further improvement in the mental health of Australians;
c. That mechanisms be put in place to foster cooperative interactions between all neuroscientists for the national good;
d. That a virtual Australian neuroscience institute be established with appropriate networking resources to facilitate cooperation in the national neuroscience effort; such a virtual institute would also provide a focus for international recognition of Australian neuroscience in a more appropriate form than the interstate competition for hegemony that might be seen to be emerging from current developments.

4. Brilliance:

In its rush to get weaving, the Working Party seems to have passed over the most  brilliant Australian minds who are studying the mind. I find it rather stressful to have been put in a position where I am forced to be my own advocate in this way, but the speed and bias of the process seem to have left me with little choice.

Recommendation 4:
That inputs be sought and incorporated from demonstrably brilliant Australian minds studying the mind, such as Profs. Allan Snyder FRS and Prof. Mandayam Srinivasan FRS.

5. Overlap:

I understand that Profs. Bennett and Hickie are now working together in Sydney toward a common goal at the same institution, although the use of the beyondblue job title in the terms of reference could give a different impression. Is this intended?

Recommendation 5:
That Prof. Hickie declare his current or intended affiliation. If Prof. Hickie clarifies things in this way, this might also set a good example for the NSVictorians on the Working Party.
 

Comments and Recommendations on Specific Areas of Basic Research relevant to Mental Health:.
 

Genotype vs Phenotype:

 The familiar nature-nurture debate has taken on a new form as resource-hungry genotyping exercises compete with less glamorous phenotypic rulers in the hunt to identify the predisposing factors that could be used in preventative mental health strategies.
 It seems obvious that a phenotypic ruler is a preferable tool to investigate the multigenic trait of height, compared with the very high cost of getting the answer from a study of the myriad of genes involved, even when one extrapolates the downward trend in genome scanning costs. Perhaps a similar conclusion can be reached from consideration of a predisposing psychiatric trait that is produced by a large number of genes. This seems to be the case for rivalry switch rate, a new trait marker for bipolar spectrum disorders with applicability to a number of other psychiatric conditions and drug-indued mental states.
Multi-genic Inheritance in Rivalry Switch Rate:
Twin and sibship studies of the perceptual rivalry switch rate trait show that it is robustly stable in an individual and highly heritable, but determined by a very large number of genes. Estimating the total number of genes will require the study of thousands of sib pairs because of the very low correlation between sib pair switch rates compared with the high correlation in monozygotic twins. A similar timing measure in E. coli (switch time between stop and  go of around 1.5 sec) involves thousands of genes,  since around one third of the E. coli genome has to be eliminated before there is any affect on the timing of this robustly-buffered genetic trait! It is not reasonable to propose that humans have fewer genes involved in rivalry switch rate than E. coli does for a similar timing trait, so neural timing may be determined by the interactions of a few thousand genes.
 The significance for psychiatry of the multigenic determination of the rivalry switch rate is that this trait has proved to be predictive and diagnostic of psychiatric conditions such as bipolar disorder, bipolar depression, dissociative identity disorder and first break schizophrenia. As a simple measure that is continuous on a second by second basis, it also has an important role in the monitoring of mental state, such as at the transition to psychosis  or in response to medications. Where clinical diagnosis is unclear, rivalry switch rate also offers a heuristic to guide long-term management, which is quite different in faster-than-normal switch rate conditions (the schizophrenogenic group) and slower-than-normal switch rate conditions (the bipolar spectrum) despite similar management of the acute psychotic crisis in both. Switch rate is also used to monitor response to treatment,  being  strongly affected by some medications.
 The controversial anti-acne medication, isoretinoin (Roacutane) for example, causes a striking reduction in switch rate in some individuals who already have a below-normal switch rate; and are then much more likely to suicide. The relatively small proportion of vulnerable individuals in the population with such low switch rates can thus be detected and the controversy over whether the drug causes suicide settled by identifying those in which it does enormously increase the risk. As well as demonstrating the heuristic power of using the phenotypic switch rate trait in a mental health context, these observations underline the physiological complexity of the switch whose many unusual features now include retinoic acid, a morphogen that is normally thought of in an embryological context but which is present in a very few locations in the adult brain:- viz: limbic cortex and the ventral tegmentum, where recent brain scanning data and comparative studies of this phylogenetically-conserved  apparatus locates the switch!  The finding of an embryologically active area in the adult brain that produces retinoic acid and is also responsible for a core aspect of neural timing that is perturbed in so many psychiatrically-relevant conditions thus emphasises the epigenetic nexus between brain plasticity and developmental mechanisms. This nexus could serve as a focus for molecular studies which would be appropriately targeted and guided in an efficient and directed way.

Recommendation 6:
a. That the costs of human genomics studies be reviewed in a national and international context; (issues to be considered would include the forward projection of these burgeoning costs; economies of scale and the possibility that it might be more cost-efficient to have gene scans performed overseas at very large efficient installations ....... Like the Dutch airlift where the Netherlands parliament decided that it was cheaper and better to fly all their coronary bypass patients to the fabulously-gifted ambidexterity of Denton Cooley than it was to build its own coronary bypass unit; the problem of competition for resources with more productive but less glamorous phenotypic studies )
b. That appropriate recognition be given to the essential role of developing finely-graded  phenotypic rulers to avoid the disproportionate costs of open-ended gene hunting where there are a very large number of genetic determinants.
c. That special attention be given to the complex task of defining phenotypic neural interactions with the environment and the cellular and molecular basis of neural plasticity  in which Australian neuroscience has fundamental strengths that relate directly to mental health.
 

Nutrition:
To those who express skepticism about the simple-minded nutritional approach to mental health, I point out the very low costs of drawing a blank in this kind of research compared with the huge waste piles of Eppendorf tips and other expensive paraphernalia that mark the graves of failed fishing expeditions for the gene that underlies bipolar disorder.

French and Scottish experience has shown that small measures with dietary anti-oxidants translate into significant gains in the demographics of dementia. Similarly, large gains across the mental health of the nation could follow the introduction of the new information that dietary intake of the essential omega-3 polyunsaturated fatty acids is important for the normal function of the rivalry switch. For example, in a large US replication of my finding that bipolar disorder is associated with a slower switch, it was also apparent that control mid-Western Americans had more overlap between their switch rates than did the Australian controls. Bipolar values were strikingly similar (and slower) in both Australian and US patients. The US sample was from the mid-West where omega-3 deficiency is subject to the triple whammy of:- 1. reduced intake of fresh sea food; 2. a historical reduction of omega-3 concentrations in the membranes of grain-fed beef compared with higher concentrations in the old-fashioned range-fed meat; 3. negative interaction with the high intake of saturated fats. Research is in progress to test the inference that diet has been responsible for the unhealthy switch of US mid-Westerners. In the meantime, it is worth considering whether the controversial post-war increase in  psychiatric disorders in OECD countries (assuming that this is not a reporting artefact) is related to the cessation of Vitamin A supplements (e.g. cod liver oilÖwidely regarded by the older generations as ìbrain foodî and certainly a source of omega-3 PUFAs), once Vitamin A was added to food.
 There is inceasing recent support from many directions for this conjecture linking omega-3s to mental health via a sticky switch (some of my brilliant patients refer to EPA and DHA as the WD40 of the brain, a colourful reference to their ability to fluidize membranes and thereby facilitate intracellular signaling). For example there are a number of cases where administration of the eicosanoid  omega-3, EPA, led to spectacular resolution of psychosis in mothers-to-be unable to receive conventional anti-psychotics because of danger to the foetus. Studies showing the role of EPA and DHA in the amelioration of depression are starting to burgeon since Stoll's landmark paper and my own work suggests that DHA and EPA may be unique in being able to speed up an otherwise robustly stable switch rate.
 There are many uncertainties in this area, not the least of which is the question whether DHA and EPA are indeed essential or whether they can be converted from linolenic acid in the diet. The controversies in this area are possibly the result of marked individual variation in the interconvertibility of the different omega-3. Given the complexities of the synthesis, I am suspicious of the studies purporting to show that c-18 omega-3 PUFA such as linolenic acid found in most plant sources can be converted into c-20 because of the failure of c-18 to show any effect on the nervous system compared with the c-20 moecules EPA and DHA. Research by Australian experts in the field, such Dr. Andy Sinclair RMUT, could clarify these issues.
 Since EPA and DHA are beneficial in other areas besides mental health such as cardiovascular health and arthritis, and since implementation in the nutritional area could be cheap and widely effective, research on these molecules  has a very low cost-benefit ratio. Except for my own studies, I am not aware of an other Australian research efforts to explore EPA and DHA in a psychiatgric context, despite rapidly-growing interest overseas and strong awareness by the general public. Even Tip Top bread has instituted omega-3 supplementation, choosing EPA and DHA as the key molecules!
 The Okinawa human longevity records are now thought to be due, in some part, to the very diverse range of different anti-oxidants that Okinawans consume compared with the less catholic range of dietary anti-oxidants in the West, a range which reaches its narrowest in the US fast food culture. I think that we should celebrate any life-style process that enriches the brain culturally while at the same time providing it with healthy molecules.

Recommendation 7:
That recognition be given to the possible role of nutritional factors in mental health, particularly in  age-related conditions like the dementias ;
That specific attention be focused on the omega-3 fatty acids, eicosopentanoic acid (EPA)  and dihydrohexanoic DHA and the extent to which they are essential, or whether they can be synthesized from precursors in the human body, and the role of EPA and DHA in normal brain function;
 

Ophthalmic Science as Neuroscience:

Ophthalmic researchers often feel left out of neuroscience fray, despite the fact that the retina is part of the brain and the fact that the visual system occupies such a disproportionately large fraction of the cerebral hemispheres. There are many examples where ophthalmic scientists directly contribute to the general understanding of the brain and mind. These incude:- Evidence of a complex multi-level organisation for aspects of visual perception formerly thought to be early sensory processes; the important role played by the oculomotor system in the measurement of efference copy, a key feature in Frith's formulation of psychosis; oculomotor signs in the early detection of dementia; retinal neurodegeneration as an accessible model system; etc  As a specific lesson in making Australian neuroscience more inclusive, the active participation of ophthalmic scientists should specifically be sought.

Recommendation 8:
That specific recognition be given  to ophthalmic scientists in the national neuroscience effort.

Neuroimaging Studies:

 fMRI:
Expensive magnets are very fashionable, with most US departments of psychiatry already having a magnet for MRI brain scanning studies, or striving to get one. Nevertheless, the general enthusiasm for fMRI tends to distract from its limitations. In the rush to join the bandwagon and to collect data with existing protocols, in only rare instances does one find research efforts to improve the dismal temporal resolution of fMRI whose BOLD signal peaks 5-8 seconds after the increase in neural activity that is being measured. Psychotic processes, such as interhemispheric attentional switches, are too fast to be captured by the BOLD signal changes, so there is an urgent need for higher temporal resolution if fMRI is to be really useful in a mental health context. This need is being addressed at a few centers (e.g. Tubingen, Gainesville, Brisbane) by fundamental research on other magnetic metalloproteins besides desoxyhaemoglobin. This is an example where support for research at a fundamental level is required. Molecular MRI studies of neural metalloproteins are unlikely to be on the radar screen of most mental health professionals, yet could be crucial for real advances in brain scanning in the mental health context (see Confidential HFSP Proposal-Attached).

Recommendation 9:
a. That basic research on the fundamentals of MRI be supported in addition to the funding of the use of the limited existing technology
b. That more research magnets be made available that are freed from the constraints that operate when research and clinical use compete.
c. That time and motion studies be undertaken to show how to utilize magnets more fully in order to offset the infrastructural costs of MRI (e.g. larger throughput, round the clock useage at night).
 

Hallucinogenic (Entheogenic) drugs:

Short-lived psychosis can be produced by 5HT analogues in normal human observers. This neuropharmacological approach is a powerful tool for studying all aspects of psychosis such as predisposition, underlying brain mechanisms, long term sequelae,  etc but is not available in Australia because we have followed the US lead in severely restricting access to such agents. By contrast, Switzerland has a more enlightened attitude and is making strides in the understanding of schizophrenia using 5HT agonists.

Recommendation 10:
To permit further research by bona fide investigators on this class of drugs, that Australia relax the draconian restrictions on entheogens that have been borrowed from the hypocritical regulation of the US DEA

Comparative Neuroscience:

The mind and brain evolved. This fact can be used to advantage by Australian neuroscientists with their unique access to an extraordinarily diverse variety of vertebrate and invertebrate brains. This is a source of great envy to our international competitors and an opportunity for ourselves. Evolutionary studies of the brain often seem to be overlooked,  for obscure reasons that may be connected to the religiosity that suffuses Australian political life and the closet creationists that still wreak havoc within universities.
 It is time to embrace the neural biodiversity offered in Australia and make explicit the advantages to be gained by neuroscience in a comparative context, both because of the unbeatable international edge that it can provide, but also because of its proven past record in providing crucial, explanatory, model systems, such as the squid giant axon that was used to solve the puzzle of the action potential by Nobel laureates Hodgkin and Huxley.
 We will need more than model systems of the action potential to solve problems of mind. An important area for mental health is the control of emotion, increasingly recognised to be a core brain function rather than an add-on.  The core brain structures for survival and metabolic activities that underly emotion (e.g. limbic system) are phylogenetically-conserved circuits that can be dissected and understood using a variety of preparations that share a common framework (such as the coordination of interhemispheric activity),  but each has different technical advantages. I got a standing ovation recently at MIT for my Fish on Prozac study, a self serving comment provided to contrast this approval with the ambivalence encoutered in a less intellectual  milieu. The midbrain interhemispheric switch of the sandlance shares numerous functional and pharmacological features with the same region of humans but has numerous technical advances including the ability to place the whole tiny brain on the stage of a confocal microscope.
 Fish neurobiology is but one example from a host of comparative neuroscience approaches of this kind where Australians can wield an unbeatable edge. Others include:- the exploitation of conotoxins from reef mollusks, studies in reef fish of the regeneration of hair cells that are structurally identical to those in the human cochlea , evolutionary studies of brain lateralisation, evolution of visual cortical areas, optic nerve regeneration in reptiles, spinal cord regeneration and early visual system plasticity in marsupial fetuses.

Recommendation 11:
10a. That suitable recognition and support be given to the further development of models of nervous system function based on the comparative method, taking full advantage of the diverse model brain systems available to Australian neuroscientists.
10b. That we not be apologetic about this undeniable advantage, but instead seek to advance evolutionary arguments that illuminate brain structure/function relationships.
 
 

Cultural Imperatives and Mental Illness:

 As I write this submission it is the anniversary of Virginia Woolfís death and an Australian actress is being feted, Oscar and all, for a shallow, unidimensional  portrait of one of the greatest minds of the twentieth century. The manic-depression of Woolf, like similar illnesses in Winston Churchill, Teddy Roosevelt, Isaac Newton, etc etc, was inextricably linked to the heights of intellectual achievement. In its demeaning portrait, with its voyeuristic concentration upon her suicide and its possible connections to the parallel fictitious lives in the screenplay, Hollywood adopts a simplistic, maudlin approach that I believe would have been as effective as the deepening shadow of Hitler over Europe in driving Woolf to suicide, had she been living today.
 The manic-depressive brain is up to an order of magnitude more sensitive than the population mode, an excruciating but inevitable outcome of the longer time constant of its signaling pathways. This is the fundamental explanation for Virginia Woolf's painful perspicacity of the human condition, an extreme sensitivity that confers interlocking advantages and disadvantages, most of them unalterable, with which one must come to terms, just as one does with other personal characteristics such as one's height.  Having heard some of the Working Group's members publicly grandstand on mental illness, I would respectfully like to point out that these appeared to my own, perhaps over-sensitive, brain as the cultural equivalents of advocating the possibility that dramatic technical advances will enable us to change the height of individuals rather than the height of the doorways.
 I have written elsewhere about how the Western approach to depression may actually be exacerbating the epidemic that confronts us by demonizing depression in a way that distracts attention away from the very real deteriorations in the culture around us.(www.uq.edu.au/nuq/jack/bipolardisorder.html). Those deteriorations will first be detected by the sensitive brains in the community, for whom medications may not be an adequate substitute for making real changes in the stressors they encounter in their daily lives.
  The composition of the Working Group, the process by which it was constituted, its reflection of an established point of view and its apparent readiness to overlook or to come very lately to those with truly original if uncomfortable viewpoints, could all be seen as a precipitating epigenetic stressor for any sensitive brain. The process would thus exacerbate the very problems that it was supposed to address! By excluding from its ranks the two most distinguished (I am talking about the FRS gong in this case as we have no Nobel laureates in the area), and brightest, minds who study minds the Working group could be seen as sending a depressing signal to a community that is hungry for real commitment to its intellectual life (such as a reversal of the under-resourcing of its educational institutions, or a recognition of my above-mentioned point that we need broad fundamental support for all aspects of brain research) .  I think that there is a real danger that the Prime Minister will be presented with a bunch of glamorous solutions that might prove to be the mental health equivalent of an improved iron lung, instead of a guide for the support of the fundamental and the unexpected.

Recommendation 12:
That the Working Group be reconstituted in some way to reflect the wide constituency of Australian neuroscience and related disciplines;
One possibility here would be a two-step process with the creation immediately of the virtual Australian neuroscience institute proposed in Recommendation 3d, allowing freer interchange and ferment on the topic of mental health and neuroscience. This first phase, which could be accomplished quickly without risky long term commitment of resources, could be followed by a later, second stage of more mature recommendations that was based upon consensus. The timing of such a two-step process would also provide flexibility in a bipartisan federal context should we have regime change at home.

JPettigrew, St. Lucia, 4 April 2003